A Comprehensive Summary of the Meta-Analyses and Systematic Reviews on Platelet-Rich Plasma Therapies for Knee Osteoarthritis.

INTRODUCTION: Osteoarthritis (OA), including that of the knee joint, represents a significant proportion of musculoskeletal injuries in the Canadian Armed Forces (CAF) due to the frequent, high-stress physical activity for which member participation is necessary. Platelet-rich plasma (PRP) is a conservative, autologous treatment that has the potential to relieve symptoms and improve functionality of military members to decrease the impact of the disease and ultimately strengthen the CAF. MATERIALS AND METHODS: A search of systematic reviews and meta-analyses was conducted to determine the efficacy of PRP injections in treating knee OA. The Scopus database, PubMed database, and Omni academic search tools were scoped for relevant publications. English literature, published up to and including March 2023, that investigated only clinically randomized controlled trials (RCTs) was eligible for inclusion. The results of network meta-analyses were investigated and summarized independent of reviews and non-network meta-analyses. RESULTS: A total of 225 unique systematic reviews and meta-analyses were initially identified, of which 39 publications, including 7 network meta-analyses, adhered to the defined inclusion and exclusion criteria. PRP was found to significantly alleviate symptoms of pain based on the visual analog scale and Western Ontario and McMaster Universities Arthritis Index pain scores within the 12-month follow-up. Function, activity, sport, quality of life, and stiffness were additionally determined to generally improve to a greater extent from PRP treatment compared to controls, while adverse effects were minor and temporary. PRP placed in the top 3 in 9 reported surface under the cumulative ranking curves, while individually reported rankings of leukocyte-poor and leukocyte-rich PRP both placed in the top 4. The clinical recommendations made were generally positive, with 17 publications acknowledging the benefits of PRP, 3 supporting possible efficacy, and an additional 8 recommending that it be an option for the conservative treatment of knee OA. CONCLUSION: The results of this review support the efficacy of PRP for relieving symptoms of pain and improving function, stiffness, and quality of life for patients experiencing knee OA within 12 months. As a result, leukocyte-poor-PRP could be considered for members of the CAF with mild to moderate knee OA (Kellgren-Lawrence grades 1-3) to slow the progression of OA and extend the military careers of CAF members. There continues to be a need for future studies to investigate the longer-term effects of PRP to verify sustained benefits at follow-up points greater than 12 months, including findings of improvement in a delayed fashion at the 3- and 6-month timeframe compared to hyaluronic acid treatment.

Comparison of Royal Canadian Navy Watchstanding Schedules.

INTRODUCTION: Life on board a naval vessel is exceptionally demanding. Workdays for naval sailors can quite easily become 18+ hours long when watch schedules, training, and drills/evolutions are taken into account. Rotating watches and short off-watch periods can force sailors into a biphasic sleep pattern that is not sufficiently restful or a rotating pattern that is impossible to adapt to. MATERIALS AND METHODS: Six different watch systems were evaluated over four separate at-sea trials. Engineering and tactical/combat departments have had different watch systems in the past because of constraints related to the specific environment in which they work. Therefore, two of the watch systems were engineering-specific watch evaluations, three of the systems were specific to tactical/combat departments, and one watch system was evaluated with the entire company of the naval vessel. RESULTS: Both two-section (1-in-2) watch systems and three-section (1-in-3) watch systems were evaluated, which involve two or three shifts of sailors rotating through a full continuous 24-h day, respectively. Moving beyond three rotations of sailors is impossible on Canadian naval vessels due to bunk space and other limitations. The best watch system that we evaluated with respect to fatigue and quality of life at sea was the 1-in-3 straight 8-h shift system that was tested for the entire ships' company. The system has a single 8-h daily watch obligation (red watch, 4:00 am-12:00 pm; white watch 12:00 pm-8:00 pm; and blue watch, 8:00 pm-4:00 am). The best 1-in-2 system was the 8-4-4-8 system in which sailors are on-watch for 8 h, off-watch for 4 h, on-watch for 4 h, and then rest for 8 h. Both of these two systems have the advantage of equitably sharing the Window of Circadian Low (from about midnight to about 8:00 am), especially when melatonin concentration in the body is usually at its peak, between 2:00 am and 6:00 am. CONCLUSIONS: The goal of this work was to comprehensively evaluate both submarine and surface fleet watch systems. We were able to develop alternative watch systems that increased Royal Canadian Navy operational readiness and improved the quality of life of our sailors at sea.

The Importance of Validating Sleep Behavior Models for Fatigue Management Software in Military Aviation.

INTRODUCTION: The propensity for air mobility missions to exhaust aircrews is strongly dependent on operational tempo. Most flying is performed during periods of low to moderate operational tempo, but a major flight safety risk can emerge when operational tempo becomes very high. This risk can be managed by software tools that contain fatigue and sleep behavior modeling, but optimization/validation of the model using the specific target population is required to ensure that the modeled predictions are accurate. The goal of the study was to validate the sleep behavior model settings for a fatigue modeling tool that is used within the RCAF, the Fatigue Avoidance Scheduling Tool, taking into account the organizational requirements for pre- and postflight routines, especially within the Air Mobility force. MATERIALS AND METHODS: Four Royal Canadian Air Force Air Mobility Squadrons from Canadian Forces Base Trenton took part in this trial over a 3-month period (May 3 to August 21, 2016). All 22 missions of the trial included long-range transmeridian flights. All members of the participating aircrew wore wrist actigraphs to measure their sleep. We compared cognitive effectiveness modeling scenarios (preharmonization) based on the SAFTE-FAST sleep behavior model with its default settings against cognitive effectiveness modeling scenarios based on actigraphically-measured sleep. The measured sleep was then harmonized against the predicted sleep to optimize accuracy of the sleep behavior algorithm. During the harmonization process, the "Autosleep" prediction settings were optimized to match the actigraphically-measured sleep timings. RESULTS: Prior to the harmonization effort, the sleep behavior algorithm overpredicted the sleep obtained by CAF Aircrews. The most significant adjustment to the sleep behavior model was the increase in commute time to account for briefing, flight planning, debriefing, and postflight activities. Following harmonization, the sleep behavior model provided nearly perfect estimates of overall fatigue risk against missions modeled with actigraphically-measured sleep. For both measured and predicted sleep, most of the time in flight was in a low-fatigue, high-cognitive effectiveness state (90%-95% cognitive effectiveness). CONCLUSIONS: Current Fatigue Risk Management Systems require accurate fatigue and sleep behavior modeling, which can only be achieved by studying specific target populations to determine their culture of work/rest routines, and optimizing sleep behavior model settings accordingly.

Blunted Nocturnal Salivary Melatonin Secretion Profiles in Military-Related Posttraumatic Stress Disorder.

Background: Sleep disturbances are a hallmark of posttraumatic stress disorder (PTSD), yet few studies have evaluated the role of dysregulated endogenous melatonin secretion in this condition. Methods: This study compared the sleep quality and nocturnal salivary melatonin profiles of Canadian Armed Forces (CAF) personnel diagnosed with PTSD, using the Clinician Administered PTSD Scale (CAPS score ≥50), with two healthy CAF control groups; comprising, a "light control" (LC) group with standardized evening light exposure and "normal control" (NC) group without light restriction. Participants were monitored for 1-week using wrist actigraphy to assess sleep quality, and 24-h salivary melatonin levels were measured (every 2h) by immunoassay on the penultimate day in a dim-light (< 5 lux) laboratory environment. Results: A repeated measures design showed that mean nocturnal melatonin concentrations for LC were higher than both NC (p = .03) and PTSD (p = .003) with no difference between PTSD and NC. Relative to PTSD, NC had significantly higher melatonin levels over a 4-h period (01 to 05 h), whereas the LC group had higher melatonin levels over an 8-h period (23 to 07 h). Actigraphic sleep quality parameters were not different between healthy controls and PTSD patients, likely due to the use of prescription sleep medications in the PTSD group. Conclusions: These results indicate that PTSD is associated with blunted nocturnal melatonin secretion, which is consistent with previous findings showing lower melatonin after exposure to trauma and suggestive of severe chronodisruption. Future studies targeting the melatonergic system for therapeutic intervention may be beneficial for treatment-resistant PTSD.

Sleep deficits in the High Arctic summer in relation to light exposure and behaviour: use of melatonin as a countermeasure.

BACKGROUND: There are conflicting reports regarding seasonal sleep difficulties in polar regions. Herein we report differences in actigraphic sleep measures between two summer trials (collected at Canadian Forces Station Alert, 82.5°N, in 2012 and 2014) and evaluate exogenous melatonin for preventing/treating circadian phase delay due to nocturnal light exposure. METHODS: Subjects wore actigraphs continuously to obtain sleep data. Following seven days of actigraphic recording the subjects filled out questionnaires regarding sleep difficulty and psychosocial parameters and subsequently remained in dim light conditions for 24 hours, during which saliva was collected bihourly to measure melatonin. During Trial 2, individuals who reported difficulty sleeping were prescribed melatonin, and a second saliva collection was conducted to evaluate the effect of melatonin on the circadian system. RESULTS: Trial 1 subjects collectively had late dim light melatonin onsets and difficulty sleeping; however, the Trial 2 subjects had normally timed melatonin rhythms, and obtained a good quantity of high-quality sleep. Nocturnal light exposure was significantly different between the trials, with Trial 1 subjects exposed to significantly more light between 2200 and 0200h. Melatonin treatment during Trial 2 led to an improvement in the subjective sleep difficulty between the pre- and post-treatment surveys; however there were no significant differences in the objective measures of sleep. CONCLUSIONS: The difference in sleep and melatonin rhythms between research participants in June 2012 and June 2014 is attributed to the higher levels of nocturnal light exposure in 2012. The avoidance of nocturnal light is likely to improve sleep during the Arctic summer.

Light treatment improves sleep quality and negative affectiveness in high arctic residents during winter.

The seasonal extremes of photoperiod in the high Arctic place particular strain on the human circadian system, which leads to trouble sleeping and increased feelings of negative affect in the winter months. To qualify for our study, potential participants had to have been at Canadian Forces Station (CFS) Alert (82° 30' 00″ N) for at least 2 weeks. Subjects filled out questionnaires regarding sleep difficulty, psychological well-being and mood and wore Actigraphs to obtain objective sleep data. Saliva was collected at regular intervals on two occasions, 2 weeks apart, to measure melatonin and assess melatonin onset. Individuals with a melatonin rhythm that was in disaccord with their sleep schedule were given individualized daily light treatment interventions based on their pretreatment salivary melatonin profile. The light treatment prescribed to seven of the twelve subjects was effective in improving sleep quality both subjectively, based on questionnaire results, and objectively, based on the actigraphic data. The treatment also caused a significant reduction in negative affect among the participants. Since the treatment is noninvasive and has minimal associated side effects, our results support the use of the light visors at CFS Alert and other northern outposts during the winter for individuals who are experiencing sleep difficulty or low mood.

Sleep and the endogenous melatonin rhythm of high arctic residents during the summer and winter.

The seasonal extremes of photoperiod in high latitudes place particular strain on the human circadian system. Arctic residence has been associated with poor sleep in both summer and winter. The goal of the work reported here was to study the circadian rhythms of individuals living in the high Arctic by measuring sleep variables and the timing of melatonin production. Two research trials were conducted in the built environment of CFS Alert (82° 29' 58″ N). Participants wore motion logging devices (actigraphs), which measure ambient light as well as motion, for 1week to provide data on sleep quantity, quality and light exposure. On the penultimate day of each trial, the participants were maintained together in a gymnasium with lounge chairs and saliva was collected at regular intervals to measure melatonin and assess the dim light melatonin onset (DLMO), offset (MelOFF), 50% rise and fall times of the whole profile and total production. In general, sleep duration was found to be significantly different between the January and June data collections at CFS Alert, with participants in June sleeping 50min on average less each day compared to their January counterparts. In June sleep was mistimed in many subjects relative to circadian phase as evidenced by the melatonin rhythm. Exposure to bright evening light was the most likely causal factor and should be avoided in the Arctic summer. The Arctic summer represents a particularly challenging environment for obtaining sufficient sleep. This has implications for the cognitive performance of staff during work hours.

An investigation of scavenger receptor A mediated leukocyte binding to polyanionic and uncharged polymer hydrogels.

Cell adhesion to biomaterials can be mediated in part by mechanisms aside from the traditionally recognized opsinization and integrin binding mechanisms. In this study, we investigated the role of scavenger receptor A (SR-A) in leukocyte binding to a series of well-controlled polyanionic and uncharged hydrogels based on a poly(N-isopropylacrylamide) backbone. The hydrogels were injected in the peritoneal cavity of SR-A knockout (KO) and wild-type mice using a minimally invasive procedure and allowed to set in situ. After 24 h, the hydrogels were recovered and analyzed, the peritoneal cavity was lavaged, and cytokine concentrations were assessed by ELISA. The polyanionic hydrogels retrieved from the KO animals were found to be completely devoid of adherent leukocytes, which were present in other materials regardless of the mouse strain in which they were injected. Results from a subsequent in vitro cellular adhesion study with a RAW264.7 cell line failed to yield a similarly definitive role for SR-A in the cellular binding of a polyanionic hydrogel. Taken together, the results of this study show that SR-A mediates leukocyte adhesion to a polyanionic hydrogel in the peritoneal cavity, but other adhesion mechanisms contribute to cellular binding in vitro.

Transient inhibition of connective tissue infiltration and collagen deposition into porous poly(lactic-co-glycolic acid) discs.

Connective tissue rapidly proliferates on and around biomaterials implanted in vivo, which impairs the function of the engineered tissues, biosensors, and devices. Glucocorticoids can be utilized to suppress tissue ingrowth, but can only be used for a limited time because they nonselectively arrest cell proliferation in the local environment. The present study examined use of a prolyl-4-hydroxylase inhibitor, 1,4-dihydrophenonthrolin-4-one-3-carboxylic acid (1,4-DPCA), to suppress connective tissue ingrowth in porous PLGA discs implanted in the peritoneal cavity for 28 days. The prolyl-4-hydroxylase inhibitor was found to be effective at inhibiting collagen deposition within and on the outer surface of the disc, and also limited connective tissue ingrowth, but not to the extent of glucocorticoid inhibition. Finally, it was discovered that 1,4-DPCA suppressed Scavenger Receptor A expression on a macrophage-like cell culture, which may account for the drug's ability to limit connective tissue ingrowth in vivo.

The recognition of biomaterials: pattern recognition of medical polymers and their adsorbed biomolecules.

All biomedical materials are recognized as foreign entities by the host immune system despite the substantial range of different materials that have been developed by material scientists and engineers. Hydrophobic biomaterials, hydrogels, biomaterials with low protein binding surfaces, and those that readily adsorb a protein layer all seem to incite similar host responses in vivo that may differ in magnitude, but ultimately result in encapsulation by fibrotic tissue. The recognition of medical materials by the host is explained by the very intricate pattern recognition system made up of integrins, toll-like receptors, scavenger receptors, and other surface proteins that enable leukocytes to perceive almost any foreign body. In this review, we describe the various pattern recognition receptors and processes that occur on biomedical material surfaces that permit detection of a range of materials within the host.

Phase advance with separate and combined melatonin and light treatment.

INTRODUCTION: Melatonin and light treatment are recommended for hastening adaptation to time zone change. We evaluated an afternoon regimen of 3 mg sustained release (SR) melatonin with and without next morning green light treatment for circadian phase advance. Effects of melatonin and light were tested separately and then combined to determine if the total phase change is additive or synergistic. MATERIAL AND METHODS: For each condition (melatonin, placebo, light, melatonin plus light), 11 subjects spent from Tuesday evening until Friday afternoon in the laboratory. For all four conditions, the following sleep schedule was maintained: night 1, 2345 to 0630 hours, night 2, 1600 to 0530 hours, and night 3, 2345 to 0700 hours. For the light-only condition, light treatment was administered between 0700 and 0800 hours on Thursday. For melatonin-only or placebo conditions, capsules were administered at 1600 hours on Wednesday. For the combined condition, melatonin was administered at 1600 hours on Wednesday with light treatment between 0600 and 0700 hours on Thursday. Circadian phase was assessed by calculating dim light melatonin onset (DLMO) from salivary melatonin, using a mean baseline +2 standard deviations (BL+2 SD) threshold. For all four conditions, pre-treatment and post-treatment DLMO assessments were on Tuesday and Thursday evenings, respectively. RESULTS: Phase advances were: melatonin at 1600 hours, 0.72 h p<0.005, light treatment from 0700 to 0800 hours, 0.31 h, non-significant, and the combined treatment, 1.04 h p<0.0002. CONCLUSION: The phase advance from the combination of afternoon melatonin with next morning light is additive.

Melatonin treatment for eastward and westward travel preparation.

INTRODUCTION: Melatonin is recommended for hastening adaptation to phase shift, but there is little information on appropriate formulations. MATERIALS AND METHODS: We evaluated the efficacy of three melatonin formulations for circadian phase advance and delay: (a) 3 mg regular release (RR), (b) 3 mg sustained release (SR), and (c) 3 mg surge-sustained release (SSR; consisting of 1 mg RR and 2 mg SR). Circadian phase was assessed by salivary melatonin dim light melatonin onset (DLMO) or offset (MelOff) using thresholds of (1) 1.0 pg/ml and (2) mean baseline + 2 standard deviations (BL + 2SD). Subjects spent from Tuesday evenings until Thursday in the laboratory. Melatonin (or placebo) was administered at 1600 hours (phase advance) Wednesday, with DLMO assessment on Tuesday and Thursday and at 0600 hours (phase delay) Wednesday, with DLMO assessment Tuesday, Wednesday, and MelOff Thursday morning. Phase advances using the 1.0 pg/ml DLMO were as follows: placebo, 0.73 h; RR, 1.23 h (p < 0.003); SR, 1.44 h (p < 0.0002); SSR, 1.16 h (p < 0.012), with no difference between formulations. RESULTS AND DISCUSSION: Similar but smaller phase advances were found with BL + 2SD. Using MelOff, posttreatment phase position for the RR formulation was delayed compared to placebo by 1.12 h (p < 0.012), 1.0 pg/ml, and 0.75 h (p < 0.036), BL+2SD. Phase shifts for the SR and SSR conditions could not be determined due to persistent high melatonin levels during sampling times. Similar phase advances were induced by all formulations, and slow clearance of slow release preparations impeded the determination of phase delays. CONCLUSION: Appropriately timed 0.5 mg melatonin doses may avoid these problems.

Timing light treatment for eastward and westward travel preparation.

Jet lag degrades performance and operational readiness of recently deployed military personnel and other travelers. The objective of the studies reported here was to determine, using a narrow bandwidth light tower (500 nm), the optimum timing of light treatment to hasten adaptive circadian phase advance and delay. Three counterbalanced treatment order, repeated measures studies were conducted to compare melatonin suppression and phase shift across multiple light treatment timings. In Experiment 1, 14 normal healthy volunteers (8 men/6 women) aged 34.9+/-8.2 yrs (mean+/-SD) underwent light treatment at the following times: A) 06:00 to 07:00 h, B) 05:30 to 07:30 h, and C) 09:00 to 10:00 h (active control). In Experiment 2, 13 normal healthy subjects (7 men/6 women) aged 35.6+/-6.9 yrs, underwent light treatment at each of the following times: A) 06:00 to 07:00 h, B) 07:00 to 08:00 h, C) 08:00 to 09:00 h, and a no-light control session (D) from 07:00 to 08:00 h. In Experiment 3, 10 normal healthy subjects (6 men/4 women) aged 37.0+/-7.7 yrs underwent light treatment at the following times: A) 02:00 to 03:00 h, B) 02:30 to 03:30 h, and C) 03:00 to 04:00 h, with a no-light control (D) from 02:30 to 03:30 h. Dim light melatonin onset (DLMO) was established by two methods: when salivary melatonin levels exceeded a 1.0 pg/ml threshold, and when salivary melatonin levels exceeded three times the 0.9 pg/ml sensitivity of the radioimmunoasssy. Using the 1.0 pg/ml DLMO, significant phase advances were found in Experiment 1 for conditions A (p < .028) and B (p < 0.004). Experiment 2 showed significant phase advances in conditions A (p < 0.018) and B (p < 0.003) but not C (p < 0.23), relative to condition D. In Experiment 3, only condition B (p < 0.035) provided a significant phase delay relative to condition D. Similar but generally smaller phase shifts were found with the 2.7 pg/ml DLMO method. This threshold was used to analyze phase shifts against circadian time of the start of light treatment for all three experiments. The best fit curve applied to these data (R(2) = 0.94) provided a partial phase-response curve with maximum advance at approximately 9-11 h and maximum delay at approximately 5-6 h following DLMO. These data suggest largest phase advances will result when light treatment is started between 06:00 and 08:00 h, and greatest phase delays will result from light treatment started between 02:00 to 03:00 h in entrained subjects with a regular sleep wake cycle (23:00 to 07:00 h).

Biomaterials, fibrosis, and the use of drug delivery systems in future antifibrotic strategies.

All biomaterials, when implanted into the body, elicit an inflammatory response that evolves into fibrovascular tissue formation on and around the material. As a result, material scientists and tissue engineers should be concerned about host response to tissue-engineered constructs that have a biomaterial component, because the host response to this component will interfere with device function and reduce the lifespan of tissue engineering devices in vivo. The fibrotic response to biomaterials is not unlike pathological fibrosis of the liver, lung, kidney, and peritoneum in many ways: i) the presence of mononuclear leukocytes are common in the local environment of both pathological fibrosis and biomaterial-induced fibrosis even though cells of mesenchymal origin are responsible for laying the majority of the extracellular matrix; ii) paracrine-signaling molecules, such as transforming growth factor beta;1, are essential mediators of fibrosis, whether it is pathological or biomaterial induced; and iii) injury and/or the presence of foreign materials (including bacterial components, toxins, or man-made objects) are essential initiators for the development of the fibrotic response. This review discusses mechanisms and research methodology related to pathological fibrosis that is of interest to researchers focused on biomaterials. Potential research models for the study of fibrosis from the fields of biomaterials and drug delivery are also discussed, which may be of interest to scientists working on the pathology of fibrotic disease.

SSRI effects on pyschomotor performance: assessment of citalopram and escitalopram on normal subjects.

INTRODUCTION: Standard aeromedical doctrine dictates that aircrew receiving treatment for depression are grounded during treatment and follow-up observation, generally amounting to at least 1 yr. The Canadian Forces has initiated a program to return selected aircrew being treated for depression to restricted flying duties once stabilized on an approved antidepressant with resolution of depression. The currently approved medications are sertraline (a selective serotonin reuptake inhibitor) and bupropion (noradrenaline and dopamine reuptake inhibitor). This study was undertaken to determine whether or not citalopram or escitalopram affect psychomotor performance. METHOD: In a double-blind crossover protocol with counter-balanced treatment order, 24 normal volunteer subjects (14 men and 10 women) were assessed for psychomotor performance during placebo, citalopram (40 mg), and escitalopram (20 mg) treatment. Each treatment arm lasted 2 wk, involving a daily morning ingestion of one capsule. There was a 1-wk washout period between medication courses. Subjects completed a drug side-effect questionnaire and were tested on three psychomotor test batteries once per week. RESULTS: Neither citalopram nor escitalopram affected serial reaction time, logical reasoning, serial subtraction, multitask, or MacWorth clock task performance. CONCLUSIONS: While we found some of the expected side effects due to citalopram and escitalopram, there was no impact on psychomotor performance. These findings support the possibility of using citalopram and escitalopram for returning aircrew to restricted flight duties (non-tactical flying) under close observation as a maintenance treatment after full resolution of depression.